De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism
| Autor: | Susan E. Holder, Claudio Graziano, Véronique Lefebvre, Joshua D. Smith, Ash Zawerton, Lisa Wischmann, Susanne J. Kühl, John Dean, Tommaso Pippucci, J. Paige Yeager, Deciphering Developmental Disorders Study, Daniela T. Pilz, Baojin Yao, Abdul Haseeb, Alisdair McNeill |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Transcriptional Activation Heterozygote In silico Xenopus Mutation Missense Biology Xenopus Proteins Article SOXC Transcription Factors Cohort Studies 03 medical and health sciences 0302 clinical medicine Neurodevelopmental disorder medicine Genetics Coffin-Lowry Syndrome Missense mutation Animals Humans Abnormalities Multiple Amino Acid Sequence Child Transcription factor Exome sequencing Genetics (clinical) Conserved Sequence SOX Transcription Factors Reporter gene Neurogenesis Correction DNA medicine.disease biology.organism_classification 030104 developmental biology Neurodevelopmental Disorders Child Preschool HMG-Box Domains Female 030217 neurology & neurosurgery |
| Zdroj: | American journal of human genetics. 104(2) |
| ISSN: | 1537-6605 |
| Popis: | SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|